Neurodegenerative disease is the disease caused by progressive lesions of nervous system, including Alzheimer's disease, Parkinson's disease. Huntington's disease, amyotrophic lateral sclerosis (ALS), ischemic or hemorrhagic stroke, etc. Since the cause of the disease is complex and the pathogenic mechanism is not very clear, there is no effective therapeutic at present.
FKBPs, which is named because of its binding with immunosuppressant FK506, is an important mediator enabling FK506 to exert immunosuppressive function, however, its physiological function has not yet been fully explained. In 1992, Steiner J. P. et al. found that the concentration of FKBPs (FKBP family) in brain and periphery nervous system was much higher than that in immune tissues, which leads to speculation that there is a certain relationship between FKBPs and nervous system. The research results of Dawson, et al. showed that FK506 could block nervous excitotoxicity caused by activation of NMDA receptor by glutamate. It is speculated that FK506 might increase phosphorylation of nitric oxide synthase (NOS) after inhibiting Calcineurin, and inhibit the catalytic activity of NOS, thus prevent neurons from being injured by NO. In addition, researches showed that GAP43, which was closely related to neurons, was also a substrate of Calcineurin. The regeneration of injured facial nerve and sciatic nerve always accompanied with obvious increase in mRNA level of GAP43, meanwhile, the mRNA level of FKBPs is correspondingly increased. These research results indicated that FKBPs might have certain relationship with the growth of nerves, and finally inspired people to find out organic small-molecular compounds, which were capable of promoting the growth of nerves, from ligands of FKBPs, and FKBPs were therefore also called as neuro-immunophilins.
Directed by the view mentioned above, in 1994, the study of Lyons, et al. showed that the immunosuppressant FK506 had significant in-vitro activity of promoting the growth of the nerves, and initiated the research on organic small-molecular nerve growth promoter. Although the mechanism of promoting the growth and protection of nerves by the ligands of FKBPs family had not been completely understood, more and more researches showed that FKBPs participated in and mediated the process. The biological evaluations, including in-vitro tests (chicken embryonic dorsal root ganglion growth, PC12 cell differentiation, oxidative injuries of nerve cell strains, etc.) and a variety of animal models (a rat peripheral sciatic nerve injury model, a diabetic rat peripheral nerve degeneration model, a Parkinson's disease animal model, an Alzheimer's disease animal model and the like), showed that some compounds designed and synthesized based on the structure of FKBPs had significant effects of promoting the growth and protection of nerves. The typical compound is GPI11485 of Guilford Pharmaceuticals Inc., according to the company, the phase II clinical researches of GP11485 as a therapeutic for prevention or treatment of Parkinson's disease and stroke has been completed, and the phase III clinical researches are also ongoing. Simultaneously, a large number of high-activity compounds continue to emerge, thereby enabling FKBPs to become important targets of the pharmaceuticals for prevention or treatment of the neurodegenerative disease.
Chinese patent application No. 01142744.2 (Substituted hexa azacyclo compounds and their use as neuroregulator) discloses FKBP ligands with brand-new structure and capable of promoting nerve regeneration, wherein the compound 4 is an optimal compound. However, researches showed that, the compound had poor blood-brain barrier permeability, and due to the low melting point and being oil state at normal temperature, the compound was not suitable for preparation of pharmaceuticals for prevention or treatment of neurodegenerative disease.
Thus, there is a need to find and develop a novel compound with enhanced permeability of blood-brain barrier and useful in prevention or treatment of neurodegenerative disease.